The serotonin type 1B (5-HT1B) receptor has been implicated in the pathogenesis of major depressive disorder (MDD). Highest concentrations of 5-HT1B receptors are found in the globus pallidus in humans. The globus pallidus has received attention recently given its functional and anatomical connection to the mesolimbic circuit which is believed to be involved in the pathophysiology of MDD. Abnormal modulation of neurotransmitter release as a consequence of dysfunctional 5-HT1B receptors in the neuronal circuits which have been shown to play a role in the pathophysiology of MDD may at least partially explain the potential neurophysiologic dysfunction underlying depression. The 5- HT1B receptor may also be a candidate target for drug development. Even though animal studies and studies in human suggest an important role for the 5-HT1B receptor in the pathogenesis of MDD it is not clear at all whether such models constitute relevant models for MDD in humans. The selective 5-HT1B receptor radioligand, [11C] CE-142,943, permits for the first time in vivo assessment of central 5-HT1B receptor binding using positron emission tomography (PET). This proposal is a 2-year study involving 10 medication-free, symptomatic subjects with current MDD according to DSM-IV criteria, and 10 individually matched healthy control subjects. All subjects will undergo one magnetic resonance imaging (MRI) scan, and one [11C] CE-142,943 PET scan under resting conditions. This study will provide important new information about the role of 5- HT1B receptors in the pathophysiology of MDD. Moreover, we believe that this study will generate important novel results which we plan to use as basis for subsequent studies that aim to determine the abnormal processes which underlie mood disorders, guide initial dosing of new therapeutic agents and that are central to predict symptom onset, monitor disease progression and assess the efficacy of therapeutic agents. PUBLIC HEALTH RELEVANCE: The neurotransmitter serotonin plays an important role in the development of depression. Serotonin is one of the brain's natural chemicals. Serotonin binds to serotonin receptors (binding sites) type 1B on brain cells to regulate emotion, anxiety, sleep, and stress hormones. With the use of positron emission tomography (PET) and administration of a radiotracer, we are able to measure the number of serotonin 1b receptors in the brain. Following the injection of the radiotracer, the PET scanner will detect the radiotracer present in brain areas. This information will be used to create pictures of the brain showing the distribution of serotonin type 1B receptors in the brain. This method allows to determining whether people with depression show a different number of serotonin 1b receptors in the brain as compared to healthy people without depression or other psychiatric illnesses. This study will help not only to learning more about the biology of depression, but may ultimately help to find better treatments for people with depression.